1. Field of the Invention
The invention relates to brevetoxin derivative compounds, pharmaceutical formulations comprising the brevetoxin derivatives, and methods of treating diseases that are related to decreased mucus transport using the compounds and pharmaceutical formulations.
2. Description of the Related Art
Decreased mucus transport is characteristic of conditions and diseases such as airway obstruction, asthma, increased incidence of pulmonary disease and/or infection, and cystic fibrosis. In particular, cystic fibrosis is characterized by abnormal functioning of the airway epithelial cells. Cystic fibrosis (or “CF”) is caused by a defective gene that codes for a Na+/Cl− transporter present on the surface of the epithelial cells that line the trachea, lungs, and other organs, including the intestines, pancreas, reproductive organs, and kidneys. Hundreds of mutations have been identified in this gene, all of which result in defective transport of sodium and chloride by epithelial cells. The severity of the disease symptoms is related to the inherited gene mutation or mutations. These observations indicate that activation of sodium channels can lead to bronchoconstriction and, in some cases, defects in mucus transport, both of which are associated with airway diseases, including CF.
The class of compounds known as the brevetoxins were initially discovered when they were purified as toxins from cultures of the Florida red tide organism Karenia brevis also known as Gymnodinium breve and Ptychodiscus brevis (Baden, D. G., et al., Toxicon, 1982; 20(5):929-932). K. Brevis proliferates during red tide incidents. The brevetoxins, also known as “PbTx” toxins (Ptychodiscus brevis toxin), have since been characterized and found to be polycyclic-polyethers that initially were shown to have binding activity to a unique site associated with rat brain synaptosomes (Poli, M. A., et al., Molec. Pharm., 1986; 30:129-135). Brevetoxins are classified as neurotoxins that are known to bind to voltage gated sodium channels. In particular, the effects of brevetoxins are mediated by interaction with receptor site 5 on the sodium channels. The general brevetoxin A and brevetoxin B backbone structure are as follows, with PbTx molecules (1-10) described.
Brevetoxin B Backbone
    PbTx-2: R is CH2C(═CH2)CHO;    PbTx-3: R is CH2C(═CH2)CH2OH;    PbTx-5: R is CH2C(═CH2)CHO, and OAc (instead of OH) at C37;    PbTx-6 R is CH2C(═CH2)CHO, and an epoxide at C27, C28 (instead of double bond);    PbTx-8 R is CH2COCH2Cl    PbTx-9 R is CH2CH(CH3)CH2OH.Brevetoxin A Backbone
    PbTx-1: R is CH2C(═CH2)CHO;    PbTx-7: R is CH2C(═CH2)CH2OH;    PbTx-10 R is CH2CH(CH3)CH2OH.
Generally, the activity of brevetoxins is thought to derive from the general backbone structure. Ring A and intact rings H, I, J, and K have been reported to be essential for the toxic activity of these compounds. There have been no reports that link toxic activity of brevetoxins to the various side chains appended to the backbone structure.
β-Naphthoyl-PbTx-3 is a brevetoxin derivative that reduces sodium channel openings and effectively antagonizes the actions of the native toxin in channel activation (Purkerson-Parker, Chemistry and Biology, 2000; 7(6):385-393). β-Naphthoyl-PbTx-3 is thought to displace the native toxin from its binding site, does not elicit opening of sodium channels in the steady state, and findings indicate that it blocks brevetoxin-induced opening of sodium channels.
If activation of voltage gated sodium channels causes airway related diseases or conditions, effective modulation or blockade of voltage gated sodium channels can be useful in alleviating airway pathologies associated with mucociliary dysfunction, such as asthma, chronic obstructive pulmonary diseases, pulmonary infection (e.g., pneumonia, Pseudomonas), and cystic fibrosis. Thus, there is a need for active agents that can act at the CFTR, P2Y2 receptors, A2B receptors, purinergic receptors, and chloride ion channels, binding to voltage gated sodium channels, which are useful in the regulation of mucus transport, as well as treatment or prevention of conditions or diseases associated with decreased mucus transport.